The Role of Oxidative Stress in Vascular Disease Associated with Diabetes

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (10 March 2024) | Viewed by 12878

Special Issue Editor


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Guest Editor
1. Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000‐548 Coimbra, Portugal
2. Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra, Portugal
Interests: obesity; diabetes; vascular dysfunction; oxidative stress; therapeutics; prevention

Special Issue Information

Dear Colleagues,

Obesity and diabetes are major health problems with a great impact on public health and increasingly gaining prevalence worldwide. Unhealthy diets and physical inactivity lead to obesity and subsequently induce insulin resistance which is a major risk factor for diabetes and cardiovascular diseases. Oxidative stress and inflammation are underlying mechanisms of endothelial dysfunction leading to vascular dysfunction, either of small or large blood vessels, in diabetic patients. There are several biomarkers of oxidative stress and inflammation available for assessing the therapeutic response to interventions, but few are currently recommended for clinical use. Moreover, the trend toward personalized medicine and individualized risk assessment during recent years is growing strong and various functional and imaging screening tests, including endothelial function studies, have been suggested to improve accuracy and provide the functional implications of the risk factors to monitor vascular disease.

This Special Issue will focus on the role of oxidative stress on vascular disease associated with diabetes emphasizing the need for biomarkers clinically relevant and new therapeutical interventions. The future of preventive and personalized medicine will reduce the burden of cardiovascular complications associated with diabetes.

Prof. Dr. Cristina M. Sena
Guest Editor

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Keywords

  • obesity
  • diabetes
  • vascular dysfunction
  • oxidative stress
  • inflammation

Published Papers (6 papers)

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Research

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16 pages, 2093 KiB  
Article
Diabetic Retinopathy and Regulation of Mitochondrial Glutathione–Glutathione Peroxidase Axis in Hyperhomocysteinemia
by Pooja Malaviya and Renu A. Kowluru
Antioxidants 2024, 13(3), 254; https://doi.org/10.3390/antiox13030254 - 20 Feb 2024
Viewed by 747
Abstract
Diabetic patients have elevated homocysteine levels, and hyperhomocysteinemia is shown to exacerbate mitochondrial damage, which plays a central role in diabetic retinopathy. Glutathione peroxidases (GPx) catalyze hydrogen peroxide (H2O2) reduction using glutathione (GSH) as a cofactor. GSH and GPx [...] Read more.
Diabetic patients have elevated homocysteine levels, and hyperhomocysteinemia is shown to exacerbate mitochondrial damage, which plays a central role in diabetic retinopathy. Glutathione peroxidases (GPx) catalyze hydrogen peroxide (H2O2) reduction using glutathione (GSH) as a cofactor. GSH and GPx are mainly cytosolic but are also present in the mitochondria to neutralize H2O2 produced by superoxide dismutase, and in diabetes, they are downregulated. Hyperhomocysteinemia also disrupts the balance between S-adenosyl-L-homocysteine and S-adenosylmethionine (SAM); SAM is also a methyl donor for DNA methylation. The aim of this study was to investigate the role of homocysteine in mitochondrial GSH–GPx1 regulation in diabetic retinopathy. Human retinal endothelial cells in 20 mM D-glucose + high homocysteine were analyzed for ROS, GSH and GPx in the mitochondria, and SAM levels and GPx1 promoter DNA methylation were also studied (5-methylcytosine and MS-PCR). The results were confirmed in the retina from streptozotocin-induced hyperhomocysteinemic (cystathionine-β-synthase-deficient) diabetic mice. High homocysteine exacerbated the glucose-induced decrease in GSH levels and GPx activity in the mitochondria and the downregulation of GPx1 transcripts and further increased SAM levels and GPx1 promoter DNA methylation. Similar results were obtained in a hyperglycemic–hyperhomocysteinemic mouse model. Thus, elevated homocysteine in diabetes hypermethylates GPx1 promoter, thus decreasing the mitochondrial GPx/GSH pool and exacerbating mitochondrial damage. Modulating hyperhomocysteinemia could be a potential therapeutic avenue to target mitochondrial dysfunction in diabetic retinopathy. Full article
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18 pages, 2459 KiB  
Article
Molecular Link between Glo-1 Expression and Markers of Hyperglycemia and Oxidative Stress in Vascular Complications of Type 2 Diabetes Mellitus
by Nida Ali Syed, Attya Bhatti and Peter John
Antioxidants 2023, 12(9), 1663; https://doi.org/10.3390/antiox12091663 - 23 Aug 2023
Cited by 2 | Viewed by 1188
Abstract
Chronic hyperglycemia and oxidative stress in Type 2 Diabetes Mellitus trigger cellular dysfunction via the formation of Advanced Glycation End Products (AGEs), resulting in dicarbonyl stress. Glyoxalase-1 (Glo-1) is the main defense against dicarbonyl stress. The aim of this study was to explore [...] Read more.
Chronic hyperglycemia and oxidative stress in Type 2 Diabetes Mellitus trigger cellular dysfunction via the formation of Advanced Glycation End Products (AGEs), resulting in dicarbonyl stress. Glyoxalase-1 (Glo-1) is the main defense against dicarbonyl stress. The aim of this study was to explore any cross-talk between Glo-1 and markers of hyperglycemia and oxidative stress. The siRNA-mediated downregulation of Glo-1 was performed in human microvascular endothelial cell line (HMEC-1). A Glo-1 transgenic rat model was developed. Glo-1 activity, as determined spectrophotometrically, and methylglyoxal were quantified using UPLC-MS/MS and the expression of representative markers of hyperglycemia and oxidative stress was performed using quantitative real-time PCR. A significant increase in the expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) was observed in the case of the siRNA-mediated downregulation of Glo-1 in the microvasculature model under hyperglycemic conditions (p-value < 0.001), as well the as overexpression of Glo-1 in the macrovasculature (p-value = 0.0125). The expression of thioredoxin interacting protein (TXNIP) was found to be significantly upregulated in wildtype diabetic conditions vs. Glo-1 transgenic control conditions (p-value = 0.008), whereas the downregulation of Glo-1 had no impact on TXNIP expression. These findings substantiate the role of VCAM as an important marker of dicarbonyl stress (represented by Glo-1 downregulation), as well as of hyperglycemia, in diabetic vascular complications. Our findings also suggest a potential feedback loop that may exist between Glo-1 and TXNIP, as the highest expression of TXNIP is observed in cases of wildtype diabetic conditions, and the lowest expression of TXNIP is observed when Glo-1 transgene is being expressed in absence of dicarbonyl stress. Full article
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23 pages, 2542 KiB  
Article
Polygenic Variants Linked to Oxidative Stress and the Antioxidant System Are Associated with Type 2 Diabetes Risk and Interact with Lifestyle Factors
by Youngjin Choi, Hyuk-Ku Kwon and Sunmin Park
Antioxidants 2023, 12(6), 1280; https://doi.org/10.3390/antiox12061280 - 15 Jun 2023
Cited by 5 | Viewed by 1257
Abstract
Oxidative stress is associated with insulin resistance and secretion, and antioxidant systems are essential for preventing and managing type 2 diabetes (T2DM). This study aimed to explore the polygenic variants linked to oxidative stress and the antioxidant system among those associated with T2DM [...] Read more.
Oxidative stress is associated with insulin resistance and secretion, and antioxidant systems are essential for preventing and managing type 2 diabetes (T2DM). This study aimed to explore the polygenic variants linked to oxidative stress and the antioxidant system among those associated with T2DM and the interaction of their polygenic risk scores (PRSs) with lifestyle factors in a large hospital-based cohort (n = 58,701). Genotyping, anthropometric, biochemical, and dietary assessments were conducted for all participants with an average body mass index of 23.9 kg/m2. Genetic variants associated with T2DM were searched through genome-wide association studies in participants with T2DM (n = 5383) and without T2DM (n = 53,318). The Gene Ontology database was searched for the antioxidant systems and oxidative stress-related genes among the genetic variants associated with T2DM risk, and the PRS was generated by summing the risk alleles of selected ones. Gene expression according to the genetic variant alleles was determined on the FUMA website. Food components with low binding energy to the GSTA5 protein generated from the wildtype and mutated GSTA5_rs7739421 (missense mutation) genes were selected using in silico analysis. Glutathione metabolism-related genes, including glutathione peroxidase (GPX)1 and GPX3, glutathione disulfide reductase (GSR), peroxiredoxin-6 (PRDX6), glutamate–cysteine ligase catalytic subunit (GCLC), glutathione S-transferase alpha-5 (GSTA5), and gamma-glutamyltransferase-1 (GGT1), were predominantly selected with a relevance score of >7. The PRS related to the antioxidant system was positively associated with T2DM (ORs = 1.423, 95% CI = 1.22–1.66). The active site of the GASTA proteins having valine or leucine at 55 due to the missense mutation (rs7739421) had a low binding energy (<−10 kcal/mol) similarly or differently to some flavonoids and anthocyanins. The PRS interacted with the intake of bioactive components (specifically dietary antioxidants, vitamin C, vitamin D, and coffee) and smoking status (p < 0.05). In conclusion, individuals with a higher PRS related to the antioxidant system may have an increased risk of T2DM, and there is a potential indication that exogenous antioxidant intake may alleviate this risk, providing insights for personalized strategies in T2DM prevention. Full article
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Review

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25 pages, 3368 KiB  
Review
Oxidative Stress and Its Regulation in Diabetic Retinopathy
by Cameron D. Haydinger, Genevieve F. Oliver, Liam M. Ashander and Justine R. Smith
Antioxidants 2023, 12(8), 1649; https://doi.org/10.3390/antiox12081649 - 21 Aug 2023
Cited by 7 | Viewed by 5859
Abstract
Diabetic retinopathy is the retinal disease associated with hyperglycemia in patients who suffer from type 1 or type 2 diabetes. It includes maculopathy, involving the central retina and characterized by ischemia and/or edema, and peripheral retinopathy that progresses to a proliferative stage with [...] Read more.
Diabetic retinopathy is the retinal disease associated with hyperglycemia in patients who suffer from type 1 or type 2 diabetes. It includes maculopathy, involving the central retina and characterized by ischemia and/or edema, and peripheral retinopathy that progresses to a proliferative stage with neovascularization. Approximately 10% of the global population is estimated to suffer from diabetes, and around one in 5 of these individuals have diabetic retinopathy. One of the major effects of hyperglycemia is oxidative stress, the pathological state in which elevated production of reactive oxygen species damages tissues, cells, and macromolecules. The retina is relatively prone to oxidative stress due to its high metabolic activity. This review provides a summary of the role of oxidative stress in diabetic retinopathy, including a description of the retinal cell players and the molecular mechanisms. It discusses pathological processes, including the formation and effects of advanced glycation end-products, the impact of metabolic memory, and involvements of non-coding RNA. The opportunities for the therapeutic blockade of oxidative stress in diabetic retinopathy are also considered. Full article
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21 pages, 2113 KiB  
Review
Perivascular Adipose Tissue Oxidative Stress in Obesity
by Andy W. C. Man, Yawen Zhou, Ning Xia and Huige Li
Antioxidants 2023, 12(8), 1595; https://doi.org/10.3390/antiox12081595 - 10 Aug 2023
Cited by 3 | Viewed by 1272
Abstract
Perivascular adipose tissue (PVAT) adheres to most systemic blood vessels in the body. Healthy PVAT exerts anticontractile effects on blood vessels and further protects against cardiovascular and metabolic diseases. Healthy PVAT regulates vascular homeostasis via secreting an array of adipokine, hormones, and growth [...] Read more.
Perivascular adipose tissue (PVAT) adheres to most systemic blood vessels in the body. Healthy PVAT exerts anticontractile effects on blood vessels and further protects against cardiovascular and metabolic diseases. Healthy PVAT regulates vascular homeostasis via secreting an array of adipokine, hormones, and growth factors. Normally, homeostatic reactive oxygen species (ROS) in PVAT act as secondary messengers in various signalling pathways and contribute to vascular tone regulation. Excessive ROS are eliminated by the antioxidant defence system in PVAT. Oxidative stress occurs when the production of ROS exceeds the endogenous antioxidant defence, leading to a redox imbalance. Oxidative stress is a pivotal pathophysiological process in cardiovascular and metabolic complications. In obesity, PVAT becomes dysfunctional and exerts detrimental effects on the blood vessels. Therefore, redox balance in PVAT emerges as a potential pathophysiological mechanism underlying obesity-induced cardiovascular diseases. In this review, we summarise new findings describing different ROS, the major sources of ROS and antioxidant defence in PVAT, as well as potential pharmacological intervention of PVAT oxidative stress in obesity. Full article
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26 pages, 2491 KiB  
Review
Clinical Relevance of lncRNA and Mitochondrial Targeted Antioxidants as Therapeutic Options in Regulating Oxidative Stress and Mitochondrial Function in Vascular Complications of Diabetes
by Tarun Pant, Nnamdi Uche, Matea Juric and Zeljko J. Bosnjak
Antioxidants 2023, 12(4), 898; https://doi.org/10.3390/antiox12040898 - 07 Apr 2023
Cited by 10 | Viewed by 1782
Abstract
Metabolic imbalances and persistent hyperglycemia are widely recognized as driving forces for augmented cytosolic and mitochondrial reactive oxygen species (ROS) in diabetes mellitus (DM), fostering the development of vascular complications such as diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, and diabetic retinopathy. Therefore, specific [...] Read more.
Metabolic imbalances and persistent hyperglycemia are widely recognized as driving forces for augmented cytosolic and mitochondrial reactive oxygen species (ROS) in diabetes mellitus (DM), fostering the development of vascular complications such as diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, and diabetic retinopathy. Therefore, specific therapeutic approaches capable of modulating oxidative milieu may provide a preventative and/or therapeutic benefit against the development of cardiovascular complications in diabetes patients. Recent studies have demonstrated epigenetic alterations in circulating and tissue-specific long non-coding RNA (lncRNA) signatures in vascular complications of DM regulating mitochondrial function under oxidative stress. Intriguingly, over the past decade mitochondria-targeted antioxidants (MTAs) have emerged as a promising therapeutic option for managing oxidative stress-induced diseases. Here, we review the present status of lncRNA as a diagnostic biomarker and potential regulator of oxidative stress in vascular complications of DM. We also discuss the recent advances in using MTAs in different animal models and clinical trials. We summarize the prospects and challenges for the use of MTAs in treating vascular diseases and their application in translation medicine, which may be beneficial in MTA drug design development, and their application in translational medicine. Full article
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